Tolerance to self-antigens is maintained at multiple levels. While central tolerance is essential to preventing autoimmunity, autoreactive T and B cells nevertheless are present in the peripheral repertoire. Thus, peripheral tolerance to tissue-specific and developmentally regulated antigens is necessary to sustain tissue homeostasis. In some cases, cross-reactive memory cells produced by infection are likely to be responsible for autoimmunity via recognition of self-antigens in the context of ongoing inflammatory events. We have now devised an inducible and reversible system that allows interrogation of T cell tolerance induction in endogenous memory CD8 T cells. Our data show that memory CD8 T cells responded poorly to self-antigen even when expressed by dendritic cells (DC) and despite the fact that the antigen was readily recognized by nave CD8 T cells. However, the inclusion of inflammatory signals partially overcame memory CD8 T cell ignorance of self-antigen. Thus, memory CD8 T cells were prohibited from autoreactivity in the absence of inflammation. These results led to the hypothesis that tolerance is maintained by disallowing memory CD8 T cell recognition of self antigen under homeostatic conditions. Our goal is to determine the mechanism by which memory CD8 T cells ignore direct DC antigen presentation and test whether tissue-specific antigens are also ignored. This goal will be achieved through two specific aims: Aim 1. To determine the anatomical constraints prohibiting memory CD8 T cell recognition of DC-expressed antigen. Aim 2. To determine whether memory CD8 T cells will recognize cross-presented tissue-specific antigen in the absence of inflammation. Our new system will provide a powerful tool for identifying the mechanisms by which autoimmunity may be avoided or controlled.